The purpose of this project is to increase our understanding of the interactions between the endocrine and immune systems in both experimental animals and humans. Several immune system products, such as the inflammatory cytokines, Tumor Necrosis Factor-a, Interleukin-1, and Interleukin-6 activate the hypothalamic-pituitary-adrenal (HPA) axis and through it suppress and restrain the inflammatory/immune response. Interleukin-6 is particularly potent in humans, stimulating not only ACTH and cortisol but also arginine-vasopressin (AVP) secretion. IL-6 causes profound fatigue and somnolence. Plasma interleukin-6 is elevated in glucocorticoid deficiency states and after exercise. Plasma IL-6 and TNFa are also elevated in disorders of excessive daytime sleepiness. Elevations of interleukin-6 in infectious, inflammatory, and traumatic states may explain the pathogenesis of the Syndrome of Inappropriate AVP Secretion observed in these states. We recently demonstrated that corticotropin-releasing hormone (CRH) is produced localy at sites of inflammation and has profound pro-inflammatory effects at an autocrine/paracrine level. We have called this "immune" CRH. Glucocorticoids and somatostatin suppress, and RU 486 markedly augments local secretion of immune CRH at an inflammatory site. CRH is a potent degranulator of mast cells, a phenomenon that can be inhibited by a nonpeptide CRH antagonist, specific for type 1 receptors called antalarmin. Immune CRH was found in the ovary and endometrium where it may participate in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstuation. Patients with rheumatoid arthritis have defective pituitary-adrenal axis responses to inflammatory stimuli and produce excessive amounts of immune CRH in their inflamed joints. Patients with multiple sclerosis have mild hypercortisolism, which is sustained by chronic hypothalamic AVP rather than CRH hypersecretion. The human CRH gene contains estrogen-responsive elements it its promoter region providing an explanation for the sexual dimorphism in the incidence of autoimmune/inflammatory disease. CRH antagonists may be useful in the treatment of autommune/inflammatory diseases. The stress hormones cortisol and catecholamines suppress interleukin-12 and/or stimulate interleukin-10 in human macrophages, causing a shift of the Thelper type towards humoral immunity. The same effect is observed with histamine and substance P.